Data from our laboratory and others indicates that endothelial cells (EC) from pre-existing vascular structures might not constitute the sole participants in new vessel formation. These studies have revealed that circulating cells, derived from the bone marrow and exhibiting certain features consistent with EC identity, are capable of homing to sites of neovascularization and contributing to the formation of new vessels in physiologic and pathologic circumstances. These cells, referred to as endothelial progenitors (EPC) or circulating endothelial progenitors (CEP) have been shown to participate in neovascularization in a variety of settings including ischemic tissue tumors, and the retina. The possibility that the participation of EPCs in neovascularization could be modulated to therapeutic benefit has recently been further suggested in pilot clinical trials of circulating EPC transplantation for ischemic diseases of the lower extremity and myocardium. Despite these encouraging data, however, a great deal remains unknown regarding the role of bone marrow derived cells in tissue repair and maintenance. Extensive literature reveals therapeutic potential for exploiting bone marrow derived progenitors, however the reported extent of participation of bone marrow derived cells in neovessel formation has been reported to range as high as 30 or more percent in certain studies, to close to zero in others. The mechanisms by which EPCs contribute to recovery of ischemic tissue, therefore, remain incompletely defined as does their therapeutic potential. Our preliminary data reveal that modulation of bone marrow derived progenitors is associated with improved physiologic outcome in acute and chronic myocardial ischemia. Moreover, these data also reveal that the results of gene therapy mediated therapeutic angiogenesis can be enhanced by bone marrow mobilization of EPCs. Finally, our preliminary findings provide important clues regarding potential mechanisms by which EPCs improve anatomic and physiologic outcome in ischemic myocardium, by revealing situations in which EPCs are deficient or defective, and result in poor cardiac outcome. Accordingly, in this proposal we will employ a series of in vivo and in vitro model systems to define the role of EPCs in recovery from myocardial ischemia with a goal of developing future therapeutic strategies exploiting these cells.